This application entitled "Development, Characterization, and Application of Multifunctional Antithrombogenic Silk Grafts," is a response to the Request for Applications (RFA) number RFA-OD- 09-009: Recovery Act Limited Competition: Small Business Catalyst Awards for Accelerating Innovative Research (R43). In this proposal, we seek to accelerate transitions to clinical trials with a new small diameter silk graft for blood vessels. We will focus on control of blood-silk biomaterial interactions by using a multifunctional approach for spatial regulation of material properties, biochemical functionalization, and drug loading and release from the silk grafts. This proposal addresses a critical outstanding clinical need for small diameter vascular grafts for coronary or femoral artery bypass in patients with advanced vascular disease and no suitable blood vessels to harvest, the common clinical practice. If vessels can be engineered to serve the function of native vessels, while also slowly fully integrating into the host vasculature, this would revolutionize small blood vessel surgery, reduce second site morbidity, and improve patient recovery. To address this challenge, we propose the development of a "cell-instructive" biomaterial graft using a natural biopolymer that is FDA approved, silk fibroin, combined with bioactive molecules to control blood protein and biomaterial interactions as well as recruit and guide host cells towards the formation of a blood vessel in situ. We specifically propose to develop acellular silk grafts designed to: (a) control graft protein and cellular interactions by biochemically functionalizing or loading the grafts with antithrombogenic drugs, (b) guide the formation of confluent endothelium by recruiting host cells (to provide long-term non-thrombogenicity), (c) mediate the migration and proliferation of host smooth muscle cells forming the vascular wall, and (d) degrade slowly and remodel over time for full integration and vascular function. The grafts will be studied in vitro (in tissue engineering studies with cells) and in vivo (artery replacement in a small animal model) in order to correlate protein and cellular responses to the graft parameters and optimize their design. PUBLIC HEALTH RELEVANCE: Improved options to repair and restore blood vessel function, particularly small diameter vessels, would have a significant positive impact human health. Cardiovascular disease remains a leading cause of death in the United States and coronary bypass surgery is common. The proposed approach in this program would overcome the limitations present with current coronary bypass surgeries and offer a new strategy for full regeneration of native blood vessels. The same technology has potential impact in a broader range of coatings for other medical devices, offering a range of benefits to human health and well being